The long-term objective of this career development award is to elucidate the neurobiology of Tourette Disorder (TD) by integrating genomics, transcriptomics, unique datasets, and novel analytic techniques. Dr. Fernandez is a practicing child psychiatrist at the Yale Child Study Center with a career goal to develop an independent research career as a psychiatric geneticist and advance our understanding of the molecular neurobiology of TD. He proposes to identify relevant risk genes, networks, and pathways that will clarify the genetic architecture of TD and point to potential molecular targets for improving treatments for this developmental neuropsychiatric disorder. Dr. Fernandez will accomplish these career and research objectives through a protected time period of research support, relevant course work, seminars, scientific meetings, and the combined guidance of his primary mentor, Matthew State, M.D., a leader in neuropsychiatric genetics, co- mentor Flora Vaccarino, M.D., a leader in developmental neurobiology, and collaborators (Drs. Nenad Sestan, Daniel Geschwind, and Bernie Devlin) who are experts in cortical development, gene network and pathway analysis, and statistical genetics, respectively. The specific aims and methods proposed under this award are entirely consistent with Dr. Fernandez's career and research objectives: (1) Concurrent with his recently-completed residency training, Dr. Fernandez identified rare gene copy number variants (CNVs) in TD subjects which overlapped with those seen in autism spectrum disorders (ASD) and implicated molecular pathways involved in GABA and histamine neurotransmission. The first aim is to confirm these prior CNV pathway and ASD-overlap findings in a larger independent replication cohort of TD subjects, in collaboration with the Tourette Syndrome Association International Consortium for Genetics (TSAICG); (2) the second aim is to learn methods for analyzing sequence and structural variation in the exomes of TD versus control subjects in order to identify rare de novo and inherited variants in parent-child trios. This will allow us to test hypotheses regarding the allelic architecture of TD and provide high resolution data for (3) the third aim, integrating this sequence and structural data with a unique dataset of gene expression in the developing brain to identify co-expression networks via established and novel statistical approaches; (4) finally, we will use our findings above to inform and explore hypotheses in a unique dataset of gene expression and whole genome sequence in postmortem brain tissue from TD and control subjects. Based on his prior record of research productivity, the proposed research aims, educational plan, mentorship team, and extensive resources of the Yale Child Study Center and School of Medicine, Dr. Fernandez is well-positioned to accomplish his career goal of becoming an independent physician scientist and clarifying the molecular mechanisms of TD, which hold promise to inform novel therapeutics. PUBLIC HEALTH RELEVANCE: This work will address important gaps in the knowledge base regarding genetic risk factors, developmental time course, and neurobiological basis of Tourette's disorder (TD). Results of this work will lead to the discovery of new molecular targets which can inform the development of novel therapeutic strategies for TD and related childhood developmental neuropsychiatric syndromes.